PROJECT SUMMARY/ABSTRACT Obesity and poor health behaviors are major modifiable contributors to health disparities in rural and Appalachian populations. Residents in rural and Appalachian areas experience higher rates of obesity, cancer incidence, and mortality, compared to residents in urban or non-Appalachian areas. Obesity increases the risk of 13 cancers due to excessive adiposity accumulation and abnormal metabolic modifications. Weight loss, physical activity, and healthy diet potentially attenuate the negative effects of obesity and reduce cancer risk and premature mortality. Evidence-based weight loss programs have been implemented in clinical settings and showed various health benefits. However, these programs solely focused on health-promoting resources available in urban areas and are not generalizable to rural and Appalachian populations. Therefore, developing effective strategies to provide weight loss programs for rural and Appalachian populations is an important priority. My long-term goal is to reduce cancer risk and disparities through lifestyle modifications among rural and Appalachian populations. To achieve this goal, the F99 phase focuses on understanding characteristics of rural and Appalachian populations that influence health behaviors and obesity-related health outcomes (Aim 1a), identifying targetable factors for intervention (Aim 1b), and translation of an evidence-based weight loss program to rural populations (Aim 1c). To complete Aim 1a, we will utilize 2011-2017 Behavioral Risk Factor Surveillance System data. To complete Aim 1b, we will conduct post-hoc mediation analysis using data from a completed NCI-sponsored group-randomized weight loss trial in Appalachian adults. To complete Aim 1c, I will coordinate a 15-week telephone-based pilot weight loss intervention among rural Ohio residents. This pilot study will translate an evidence-based weight loss intervention with tailored strategies for rural populations to meet their needs. We will determine the feasibility and acceptability of the intervention among rural populations. The results from studies in the F99 phase will guide the design of the intervention in the K00 phase: I will determine the dose-response effect of a weight loss intervention on cancer risk factors in rural and Appalachian populations (Aim 2). To complete this aim, I will design and conduct a pilot weight loss randomized controlled trial among overweight/obese residents in rural and Appalachian areas. The proposed research aligns with an NCI strong interest of behavioral intervention and cancer prevention across diverse populations. The proposed research and training plan will: 1) provide the multidisciplinary training necessary to accelerate the translation of research findings into the design and conduct of lifestyle interventions; 2) facilitate my long-term goal to become a successful independent investigator with a focus on lifestyle modifications and cancer prevention in rural and Appalachian populations; and 3) provide necessary experience to submit a competitive large-scale research grant (R01).